This invention relates to the use of pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic diamides for selectively inhibiting collagenase (MMP 13). The pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides can therefore be employed for treating degenerative diseases of the joints.
It is known that pyrimidine-4,6-dicarboxylic acid diamides and 2,4-substituted pyridine-N-oxides inhibit the enzymes proline hydroxylase and lysine hydroxylase and thereby bring about an inhibition of collagen synthesis by influencing the collagen-specific hydroxylation reaction (EP 0418797; EP 0463592). This inhibition of collagen synthesis results in the formation of a nonfunctional, underhydroxylated collagen molecule which can only be released by the cells into the extracellular space in small quantity. In addition, the underhydroxylated collagen cannot be incorporated into the collagen matrix and is very easily broken down proteolytically. As a consequence of these effects, the overall quantity of extracellularly deposited collagen decreases.
In diseases such as osteoarthritis and rheumatism, the joint is destroyed, due, in particular, to the proteolytic degradation of collagen by collagenases. Collagenases belong to the metalloproteinase (MP) or matrix metalloproteinase (MMP) superfamily. MMPs cleave collagen, laminin, proteoglycans, elastin or gelatin under physiological conditions and therefore play an important role in bone and connective tissue. A large number of different inhibitors of the MMPs or the collagenases are known (EP 0 606 046; WO94/28889). The known inhibitors of the MMPs frequently suffer from the disadvantage that they lack the specificity of inhibiting only one class of the MMPs. As a result, most MMP inhibitors inhibit several MMPs at the same time because the catalytic domains of the MMPs exhibit similar structures. As a consequence, the inhibitors act, in an undesirable manner, on many enzymes, including those, which have a vital function (Massova I., et al., The FASEB Journal (1998) 12, 1075-1095).
In an endeavor to find active compounds for treating connective tissue diseases, it has now been found that the compounds, which are employed in accordance with the invention are powerful inhibitors of matrix metalloproteinase 13 whereas they are essentially inactive in the case of MMPs 3 and 8.